The present invention relates to treatment of inflammatory conditions such as colitis and hepatitis.
Human inflammatory bowel disease (IBD), such as Crohn's disease (CD) or ulcerative colitis (UC), are characterized by inflammation in the large and/or small intestine associated with uncontrolled innate and adaptive immunity against normal constituents, including commensal bacteria and various microbial products (Fiocchi et al., Gastroenterology, 115:182-205 (1998); McKay, D. M., Can. J. Gastroenterology, 13:509-516 (1999); Sartor, Res Immunol., 148:567-576 (1997); Cong et al., J. Exp. Med., 187:855-864 (1998); Maaser, et al., Z Gastroenterol., 40:525-529 (2002)). Imbalance of pro-inflammatory cytokines in innate immunity has been demonstrated to play a role in the pathogenesis of IBD (Reinecker et al., Clin. Exp. Immunol., 94:174-181 (1993)). Disregulated CD4 T cells in adaptive immunity have also been postulated to play a role in the pathogenesis of IBD (Fuss et al., J. Immunol., 157:1261-1270 (1996); Braegger et al., Ann. Allergy, 72:135-141 (1994); Monteleone et al., Gastroenterology, 112:1169-78 (1997); Parronchi et al., Am. J. Pathol. 150:823-832 (1997)). Responding T cells exhibit a T helper type 1 (Th1) phenotype capable of producing interferon (IFN)-gamma in CD whereas Th2 cytokines are closely associated with UC (Fuss et al., J. Immunol., 157:1261-1270 (1996); Braegger et al., Ann. Allergy, 72:135-141 (1994); Monteleone et al., Gastroenterology, 112:1169-78 (1997); Parronchi et al., Am. J. Pathol. 150:823-832 (1997)).
A widely used animal model for UC is dextran sodium sulfate (DSS)-induced colitis. Mice that are exposed to DSS in their drinking water develop an inflammation of the colon displaying symptoms such as diarrhea, rectal bleeding, and weight loss. The histological phenotype of the acute phase of DSS-induced colitis is characterized by epithelial cell lesions and acute inflammation mainly consisting of infiltrating granulocytes and macrophages (Cooper et al., Lab Invest, 69:238-249 (1993); Okayasu et al., Gastroenterology, 98:694-702 (1990)). Lymphocytes have been described as not necessary for the acute inflammatory phase of DSS-induced colitis. Mice lacking T cells, however, do not fully recover from colitis (Dieleman et al., Gastroenterology, 107:1643-1652 (1994); Tsuchiya et al., J. Immunol., 171:5507-5513 (2003)). Exposure of animals to several cycles of DSS results in the development of chronic colitis that is associated with lymphocyte infiltrates of CD4 T lymphocytes and B cells (Dieleman et al., Clin. Exp. Immunol., 114:385-391 (1998); Teramoto et al., Clin. Exp. Immunol., 139:421-428 (2005)). A role for T lymphocytes in the remission of DSS-induced colitis is not known.
In addition to cytokine expression, chemokines and their receptors also contribute to the regulation of intestinal immune responses and mucosal inflammation. The CC chemokine receptors CCR2 and CCR5 are involved in both monocyte-mediated and macrophage-mediated immune responses, and in the regulation of T cell migration and activation. Mice deficient in CCR2 or CCR5 are protected from DSS-induced colitis (Andres et al., J. Immunol., 164:6303-6312 (2000)). Certain cytokines (such as IL-1β) contribute to disease progression and tissue damage in human inflammatory bowel disease.
T cell-mediated immune responses play a role in the development and progression of various liver diseases, including autoimmune hepatitis, viral infection, and alcoholic hepatitis (Heneghan et al., Hepatology, 35:7-13 (2002); Bogdanos et al., Dig. Liver Dis., 32:440-446 (2000); Chang, K. M. et al., Hepatology, 33:267-276 (2001); Chedid et al., Gastroenterology, 105:254-266 (1993); Kita et al., Gastroenterology, 120:1485-1501 (2001); Rehermann et al., Curr. Top. Microbiol. Immunol., 242:299-325 (2000); Eggink et al., Clin. Exp. Immunol., 50:17-24 (1982)). Concanavalin A (ConA)-induced hepatitis is a murine model of autoimmune or viral hepatitis that shares several pathological properties with human autoimmune hepatitis and viral hepatitis (Lohr et al., Hepatology, 24:1416-1421 (1996)). ConA-induced hepatitis also has been used as a model of T cell-mediated liver injury (Tiegs et al., A. J. Clin. Invest., 90:196-203 (1992)). These liver diseases are associated with the infiltration of various lymphocyte subsets including activated T cells. The infiltration of CD4 T cells into the liver is involved in human autoimmune and virus hepatitis (Chang et al., Hepatology, 33:267-276, 23 (2001); Rehermann et al., Curr. Top. Microbiol. Immunol., 242:299-325 (2000); Eggink et al., Clin. Exp. Immunol., 50:17-24 (1982)). T cells have a documented role in the pathogenesis of ConA-induced hepatitis including the induction and effector phases (Tiegs et al., J. Clin. Invest., 90:196-203 (1992); Kusters et al., Gastroenterology, 111:462-471 (1996); Mizuhara et al., Hepatology, 23:1608-1615 (1996); Toyonaga et al., Proc. Natl. Acad. Sci. U.S.A., 91: 614-618 (1994)). Pre-treatment with T cell-specific antibodies or immunosuppressive agents, such as anti-Thy-1, anti-CD4 mAb, FK506, or cyclosporine A, inhibited ConA-induced hepatitis, indicating that CD4 T cells and their activation of TCR-mediated signaling are involved in the induction of ConA-induced hepatitis (Tiegs et al., J. Clin. Invest., 90:196-203 (1992)). In addition, IFN-gamma appears to be involved in the development of ConA-induced hepatitis (Kusters et al., Gastroenterology, 111:462-471 (1996); Mizuhara et al., Hepatology, 23:1608-1615 (1996); Toyonaga et al., Proc. Natl. Acad. Sci. U.S.A., 91:614-618 (1994)). NKT cells and their production of IFN-gamma play a role in the development of ConA-induced hepatitis (Kaneko et al., J. Exp. Med., 191:105-114 (2000)).
CD69 (also known as early T cell activation antigen p60; see Mendelian Inheritance in Man I.D. No. *107273) is a type II membrane protein expressed as a homodimer of heavily glycosylated subunits (Ziegler et al., Eur. J. Immunol., 23:1643-1648 (1993)). Both T and B cells express CD69 within a few hours after stimulation. CD69 is an early activation marker antigen of lymphocytes (Testi et al., Immunol. Today, 15:479-483 (1994)). Freshly prepared thymocytes undergoing selection events express CD69 (Nakayama et al., J. Immunol., 168:87-94 (2002); Feng et al., Int. Immunol., 14:535-544 (2002)). There may be regulatory roles for CD69 expression in T cell development in the thymus, as well as a mild effect on B cell development (Lauzurica et al., Blood, 95:2312-2320 (2000)). Constitutive expression of CD69 has been noted in platelets, and activated neutrophils and eosinophils express CD69 on their cell surface. CD69 may have regulatory roles in a collagen-induced arthritis model and an anti-collagen antibody-induced arthritis model, possibly involving multiple target processes (Sancho et al., J. Clin. Invest., 112:872-882 (2003); Murata et al., Int. Immunol., 15:987-992 (2003)). The role of CD69 in other inflammatory models, such as in allergic airway inflammation, however, has not been ascertained. A function of CD69 in lymphocyte trafficking has been proposed (Shiow et al., Nature, 440:540-544 (2006)). A role for CD69 in the development of other inflammatory conditions, such as colitis and hepatitis, is unknown.
Accordingly, a need exists for new therapies for treating inflammatory conditions, such as colitis and hepatitis. New anti-inflammatory therapies employing one or more therapeutic compounds against a specific molecular target are sought.
All the patents and publications mentioned above and throughout are incorporated in their entirety by reference herein.